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During mild or moderate exercise, alveolar ventilation increases in direct proportion to metabolic rate, regulating arterial CO 2 pressure near resting levels. Mechanisms giving rise to the hyperpnoea of exercise are unsettled despite over a century of investigation. In the past three decades, neuroscience has advanced tremendously, raising optimism that the 'exercise hyperpnoea dilemma' can finally be solved. In this review, new perspectives are offered in the hope of stimulating original ideas based on modern neuroscience methods and current understanding. We first describe the ventilatory control system and the challenge exercise places upon blood-gas regulation. We highlight relevant system properties, including feedforward, feedback and adaptive (i.e., plasticity) control of breathing. We then elaborate a seldom explored hypothesis that the exercise ventilatory response continuously adapts (learns and relearns) throughout life and ponder if the memory 'engram' encoding the feedforward exercise ventilatory stimulus could reside within the cerebellum. Our hypotheses are based on accumulating evidence supporting the cerebellum's role in motor learning and the numerous direct and indirect projections from deep cerebellar nuclei to brainstem respiratory neurons. We propose that cerebellar learning may be obligatory for the accurate and adjustable exercise hyperpnoea capable of tracking changes in life conditions/experiences, and that learning arises from specific cerebellar microcircuits that can be interrogated using powerful techniques such as optogenetics and chemogenetics. Although this review is speculative, we consider it essential to reframe our perspective if we are to solve the till-now intractable exercise hyperpnoea dilemma., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle., Method: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling., Results: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression., Conclusion: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model., (© 2024. The Author(s).)

Objectives: The purpose of this study was to investigate whether people with fibromyalgia (FM) have dysfunctional breathing by examining acid-base balance and comparing it with healthy controls., Methods: Thirty-six women diagnosed with FM and 36 healthy controls matched for age and gender participated in this cross-sectional study. To evaluate acid-base balance, arterial blood was sampled from the radial artery. Carbon dioxide, oxygen, bicarbonate, base excess, pH and lactate were analysed for between-group differences. Blood gas analyses were performed stepwise on each individual to detect acid-base disturbance, which was categorized as primary respiratory and possible compensation indicating chronicity. A three-step approach was employed to evaluate pH, carbon dioxide and bicarbonate in this order., Results: Women with FM had significantly lower carbon dioxide pressure ( p = 0.013) and higher lactate ( p = 0.038) compared to healthy controls at the group level. There were no significant differences in oxygen pressure, bicarbonate, pH and base excess. Employing a three-step acid-base analysis, 11 individuals in the FM group had a possible renally compensated mild chronic hyperventilation, compared to only 4 among the healthy controls ( p = 0.042)., Conclusions: In this study, we could identify a subgroup of individuals with FM who may be characterized as mild chronic hyperventilators. The results might point to a plausible dysfunctional breathing in some women with FM., (© 2024 the author(s), published by De Gruyter.)

Objective: The objective of this study was to observe the effects of various clinical factors on the activation and appearance of epileptiform abnormalities (EAs) in routine electroencephalography (rEEG) by different provocation methods., Methods: This observational study involved a review of 136 patients presented for EEG recording due to various indications and their EEG showing EAs during various provocation methods., Results: Generalized spike-wave discharges (GSWDs) were the most frequent activated epileptiform pattern observed in, 81 (59.1%) recordings. This pattern was seen mainly in females 49 (P = 0.00), in patients with generalized seizures 48 (P = 0.00), in prolonged EEG records 3 (P = 0.03), and in both genetic 35 (P = 0.00) and lesional epilepsies 21 (P = 0.00). Focal sharp waves with bilateral synchrony (FSWSBS) were the most activated ictal pattern (P = 0.00). Ictal EAs after hyperventilation (HV) (P = 0.03) and intermittent photic stimulation (IPS) (P = 0.01) were mainly observed in patients with uncontrolled seizures (P = 0.00), and immune-mediated epilepsy (P = 0.02). Females sex (odds ratio [OR]: 1.33, confidence interval [CI]: 0.6-2.6; P = 0.25), bilateral tonic-clonic seizures (OR: 1.17, CI: 0.5-2.4; P = 0.31) and lesional epilepsies (OR: 1.45, CI: 0.7-2.9; P = 0.20) had risk of activation of EAs by provocation methods; however this risk was not statistically significant. While sleep deprivation (SD) (OR: 6.33, CI: 2.2-18.2; P = 0.00), nonrapid eye movement sleep (NREM) (OR: 2.41, CI: 1.0-5.4; P = 0.00), and prolong EEG recording (OR: 1.91, CI: 0.9-3.9; P = 0.04) were leading to a statistically significant risk of activation and appearances of EAs due to provocation., Conclusion: Different provocation methods can activate and augment the variety of EEG patterns of diverse clinical significance. Detection of activated ictal EAs is dependent on various patient factors, including seizure control, and the provocation method applied. Further larger prospective cohort studies with adequate sample sizes are warranted., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Hyperventilation-induced nystagmus test (HINT) is capable of generating a response in 77.2% of cases of acute unilateral vestibulopathy (AUVP); both nystagmus toward the affected side (excitatory pattern) and toward the healthy side (inhibitory pattern) have been described. The aim of the study is to investigate the clinical and prognostic role of the test by evaluating its correlation with vestibulo-ocular reflex (VOR) gain. We evaluated 33 AUVP patients by performing the HINT and video head impulse test (V-HIT) during the acute phase and then at 15 and 90 days after the onset of the symptoms. The correlation between the VOR gain of the affected side and test responses was evaluated first, phase by phase, and then considering the pattern shown during the first assessments. Patients with a negative HINT had a higher mean VOR gain than patients with a positive test at both 15 and 90 days. Patients who showed an inhibitory pattern at the first assessment had a continuous improvement in V-HIT performance, while patients with an initial excitatory response had a transient decrease in gain at the subsequent evaluation (P=.001). No difference between these 2 groups emerged at 90 days (P=.09). The finding of a negative HINT during the follow-up correlates with good V-HIT performance and could be an indicator of good recovery. The inhibitory pattern is associated with a subsequent improvement; and it would be indicative of compensation. but, despite this, the prognostic value of the test is limited.

The high metabolic demand of cerebral tissue requires that local perfusion is tightly coupled with local metabolic rate (neurovascular coupling; NVC). During chronic altitude exposure, where individuals are exposed to the antagonistic cerebrovascular effects of hypoxia and hypocapnia, pH is maintained through renal compensation and NVC remains stable. However, the potential independent effect of acute hypocapnia and respiratory alkalosis on NVC remains to be determined. We hypothesized that acute steady-state hypocapnia via voluntary hyperventilation would attenuate the magnitude of NVC. We recruited 17 healthy participants and insonated the posterior cerebral artery (PCA) with transcranial Doppler ultrasound. NVC was elicited using a standardized strobe light stimulus (6 Hz; 5 × 30 s on/off) where absolute delta responses from baseline (BL) in peak, mean, and total area under the curve (tAUC) were quantified. From a BL end-tidal (P ET )CO 2  level of 36.7 ± 3.2 Torr, participants were coached to hyperventilate to reach steady-state hypocapnic steps of Δ-5 Torr (31.6 ± 3.9) and Δ-10 Torr (26.0 ± 4.0; p < 0.001), which were maintained during the presentation of the visual stimuli. We observed a small but significant reduction in NVC peak (ΔPCAv) from BL during controlled hypocapnia at both Δ-5 (-1.58 cm/s) and Δ-10 (-1.37 cm/s), but no significant decrease in mean or tAUC NVC response was observed. These data demonstrate that acute respiratory alkalosis attenuates peak NVC magnitude at Δ-5 and Δ-10 Torr P ET CO 2 , equally. Although peak NVC magnitude was mildly attenuated, our data illustrate that mean and tAUC NVC are remarkably stable during acute respiratory alkalosis, suggesting multiple mechanisms underlying NVC., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively., (© 2021. The Author(s).)

New Findings: What is the central question of this study? How does sternocleidomastoid blood flow change in response to increasing ventilation and whole-body exercise intensity? What is the main finding and its importance? Sternocleidomastoid blood flow increased with increasing ventilation. For a given ventilation, sternocleidomastoid blood flow was lower during whole-body exercise compared to resting hyperpnoea. These findings suggest that locomotor muscle work exerts an effect on respiratory muscle blood flow that can be observed in the sternocleidomastoid., Abstract: Respiratory muscle work influences the distribution of blood flow during exercise. Most studies have focused on blood flow to the locomotor musculature rather than the respiratory muscles, owing to the complex anatomical arrangement of respiratory muscles. The purpose of this study was to examine how accessory respiratory (i.e. sternocleidomastoid, and muscles in the intercostal space) muscle blood flow changes in response to locomotor muscle work. Seven men performed 5 min bouts of constant load cycling exercise trials at 30%, 60% and 90% of peak work rate in a randomized order, followed by 5 min bouts of voluntary hyperpnoea (VH) matching the ventilation achieved during each exercise (EX) trial. Blood-flow index (BFI) of the vastus lateralis, sternocleidomastoid (SCM) and seventh intercostal space (IC) were estimated using near-infrared spectroscopy and indocyanine green and expressed relative to resting levels. BFI SCM was greater during VH compared to EX (P = 0.002) and increased with increasing exercise intensity (P = 0.036). BFI SCM reached 493 ± 219% and 301 ± 215% rest during VH and EX at 90% peak work rate, respectively. BFI IC increased to 242 ± 178% and 210 ± 117% rest at 30% peak work rate during VH and EX, respectively. No statistically significant differences in BFI IC were observed with increased work rate during VH or EX (both P > 0.05). Moreover, there was no observed difference in BFI IC between conditions (P > 0.05). BFI SCM was lower for a given minute ventilation during EX compared to VH, suggesting that accessory respiratory muscle blood flow is influenced by whole-body exercise., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Mechanically and metabolically sensitive thin fibre (group III and IV) muscle afferents are activated during exercise, causing reflex cardiovascular responses that are essential to normal cardiovascular control. Impaired exercise performance in some disease states can be linked to abnormal muscle mechanoreflex and muscle metaboreflex activity. A role for this same afferent feedback in contributing to the hyperpnoea of exercise and the dyspnoea experienced by some patient groups on exercise has recently received increased attention. Evidence is summarised here that supports a role for muscle mechanoreflex and muscle metaboreflex involvement in the human ventilatory response to exercise and also their synergistic interaction with the central chemoreflex during muscular activity. The effects of local muscle training induced attenuation of the human muscle metaboreflex on this synergistic interaction and associated decrease in ventilation is discussed., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

New Findings: What is the topic of this review? Elevated demand is placed on the respiratory muscles during whole-body exercise-induced hyperpnoea. What is the role of elevated demand in neural modulation of cardiovascular control in respiratory and locomotor skeletal muscle, and what are the mechanisms involved? What advances does it highlight? There is a sympathetic restraint of blood flow to locomotor muscles during near-maximal exercise, which might function to maintain blood pressure. During submaximal exercise, respiratory muscle blood flow might be also be reduced if ventilatory load is sufficiently high. Methodological advances (near-infrared spectroscopy with indocyanine green) confirm that blood flow is diverted away from respiratory muscles when the work of breathing is alleviated., Abstract: It is known that the respiratory muscles have a significant increasing oxygen demand in line with hyperpnoea during whole-body endurance exercise and are susceptible to fatigue, in much the same way as locomotor muscles. The act of ventilation can itself be considered a form of exercise. The manipulation of respiratory load at near-maximal exercise alters leg blood flow significantly, demonstrating a competitive relationship between different skeletal muscle vascular beds to perfuse both sets of muscles adequately with a finite cardiac output. In recent years, the question has moved towards whether this effect exists during submaximal exercise, and the use of more direct measurements of respiratory muscle blood flow itself to confirm assumptions that uphold the concept. Evidence thus far has shown that there is a reciprocal effect on blood flow redistribution during ventilatory load manipulation observed at the respiratory muscles themselves and that the effect is observable during submaximal exercise, where active limb blood flow was reduced in conditions that simulated a high work of breathing. This has clinical applications for populations with respiratory disease and heart failure, where the work of breathing is remarkably high, even during submaximal efforts., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Panic disorder (PD) pathophysiology is very heterogeneous, and the discrimination of distinct subtypes could be very useful. A subtype based on respiratory symptoms is known to constitute a specific subgroup. However, evidence to support the respiratory subtype (RS) as a distinct subgroup of PD with a well-defined phenotype remains controversial. Studies have focused on characterization of the RS based on symptoms and response to CO2. In this line, we described clinical and biological aspects focused on symptomatology and CO2 challenge tests in PD RS. The main symptoms that characterize RS are dyspnea (shortness of breath) and a choking sensation. Moreover, patients with the RS tended to be more responsive to CO2 challenge tests, which triggered more panic attacks in this subgroup. Future studies should focus on discriminating respiratory-related clusters and exploring psychophysiological and neuroimaging outcomes in order to provide robust evidence to confirm RS as a distinct subtype of PD.

Mammalian transcription factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities, such as Pitt-Hopkins syndrome (PTHS). Here, we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed widely in the Drosophila brain. Furthermore, silencing of da , using several central nervous system-specific Gal4 driver lines, impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and Discs large 1 (Dlg1), suggesting the involvement of Da in memory formation. Here, we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, as Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies, suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis, possibly via its synaptic target genes Syn and dlg1 These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

It is unsettled whether increased exercise ventilation in Fontan subjects is due to increased pulmonary dead space or augmented ventilatory drive. Twenty-six Fontan patients underwent symptom-limited treadmill cardiopulmonary exercise testing. Two groups of age- and sex- matched subjects served as controls: the biventricularly repaired (Bi, n = 18), and the "true" control (C, n = 29) groups. Peak oxygen uptake (V̇O 2peak ) was not different among groups (41.0 +/- 8.4 ml/min/kg, 43.5 +/- 6.6 ml/min/kg, and 45.9 +/- 11.6 ml/min/kg for Fontan, Bi, and C groups, respectively, p = 0.16). Fontan subjects, however, showed steeper alveolar ventilation/carbon-dioxide (V̇A/V̇CO 2 ) regression slope (35.5 +/- 5.3, 28.7 +/- 3.8, and 29.5 +/- 3.0 l/ml, for Fontan, Bi, and C groups, respectively, p<0.0001), and lower end-expiratory carbon-dioxide fraction (FetCO 2VAT ) at ventilatory threshold (VAT) (4.4 +/- 0.5%, 5.5 +/- 0.5%, and 5.5 +/- 0.4%, for Fontan, Bi, and C groups, respectively, p<0.001). The dead-space ventilation fraction at VAT was similar among groups (0.33 +/- 0.06, 0.33 +/- 0.04, 0.35 +/- 0.05 for Fontan, Bi, and C groups, respectively, p = 0.54). In Fontan subjects, arterial oxygen saturation at rest (SaO 2rest ) was correlated with V̇A/V̇CO 2 regression slope (r = -0.41, p = 0.04) and with FetCO 2VAT (p = -0.53, p<0.01). We conclude that Fontan patients show exercise hyperventilation due to augmented central and/or peripheral ventilatory drive, which is further augmented by residual hypoxemia., Competing Interests: None.

An increase of heart rate to physical or mental stress reflects the ability of the autonomous nervous system and the heart to respond adequately. Hyperventilation is a user-controlled breathing maneuver that has a significant impact on coronary function and hemodynamics. Thus, we aimed to investigate if the heart rate response to hyperventilation (HRR HV ) can provide clinically useful information. A pooled analysis of the HRR HV after 60 s of hyperventilation was conducted in 282 participants including healthy controls; patients with heart failure (HF); coronary artery disease (CAD); a combination of both; or patients suspected of CAD but with a normal angiogram. Hyperventilation significantly increased heart rate in all groups, although healthy controls aged 55 years and older (15 ± 9 bpm) had a larger HRR HV than each of the disease groups (HF: 6 ± 6, CAD: 8 ± 8, CAD+/HF+: 6 ± 4, and CAD-/HF-: 8 ± 6 bpm, p < 0.001). No significant differences were found between disease groups. The HRR HV may serve as an easily measurable additional marker of cardiovascular health. Future studies should test its diagnostic potential as a simple, inexpensive pre-screening test to improve patient selection for other diagnostic exams.

New Findings: What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease., Abstract: The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO 2 /H + ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Background: Pitt-Hopkins syndrome (PTHS) is a genetic neurodevelopmental disorder associated with intellectual disability. Although the genetic mechanisms underlying the disorder have been identified, description of its behavioural phenotype is in its infancy. In this study, reported behavioural and psychological characteristics of individuals with PTHS were investigated in comparison with the reported behaviour of age-matched individuals with Angelman syndrome (AS) and Cornelia de Lange syndrome (CdLS)., Methods: Questionnaire data were collected from parents/caregivers of individuals with PTHS (n = 24), assessing behaviours associated with autism spectrum disorder (ASD), sociability, mood, repetitive behaviour, sensory processing, challenging behaviours and overactivity and impulsivity. For most measures, data were compared to data for people with AS (n = 24) and CdLS (n = 24) individually matched by adaptive ability, age and sex., Results: Individuals with PTHS evidenced significantly higher levels of difficulties with social communication and reciprocal social interaction than individuals with AS, with 21 of 22 participants with PTHS meeting criteria indicative of ASD on a screening instrument. Individuals with PTHS were reported to be less sociable with familiar and unfamiliar people than individuals with AS, but more sociable with unfamiliar people than individuals with CdLS. Data also suggested areas of atypicality in sensory experiences. Challenging behaviours were reported frequently in PTHS, with self-injury (70.8%) occurring at significantly higher rates than in AS (41.7%) and aggression (54.2%) occurring at significantly higher rates than in CdLS (25%). Individuals with PTHS also evidenced lower reported mood than individuals with AS., Conclusions: Behaviours which may be characteristic of PTHS include those associated with ASD, including deficits in social communication and reciprocal social interaction. High rates of aggression and self-injurious behaviour compared to other genetic syndrome groups are of potential clinical significance and warrant further investigation. An atypical sensory profile may also be evident in PTHS. The specific aetiology of and relationships between different behavioural and psychological atypicalities in PTHS, and effective clinical management of these, present potential topics for future research.

New Findings: What is the central question of this study? What are the independent effects of hypoxia and hypocapnia on cerebral haemodynamics and cognitive function? What is the main finding and its importance? Exposure to hyperventilation-induced hypocapnia causes cognitive impairment in both normoxia and hypoxia. In addition, supplementation of carbon dioxide during hypoxia alleviates the cognitive impairment and reverses hypocapnia-induced vasoconstriction of the cerebrovasculature. These data provide new evidence for the independent effect of hypocapnia on the cognitive impairment associated with hypoxia., Abstract: Hypoxia, which is accompanied by hypocapnia at altitude, is associated with cognitive impairment. This study examined the independent effects of hypoxia and hypocapnia on cognitive function and assessed how changes in cerebral haemodynamics may underpin cognitive performance outcomes. Single reaction time (SRT), five-choice reaction time (CRT) and spatial working memory (SWM) tasks were completed in 20 participants at rest and after 1 h of isocapnic hypoxia (IH, end-tidal oxygen partial pressure ( P ET O 2 ) = 45 mmHg, end-tidal carbon dioxide partial pressure ( P ETC O 2 ) clamped at normal) and poikilocapnic hypoxia (PH, P ET O 2  = 45 mmHg, P ETC O 2 not clamped). A subgroup of 10 participants were also exposed to euoxic hypocapnia (EH, P ET O 2  = 100 mmHg, P ETC O 2 clamped 8 mmHg below normal). Middle cerebral artery velocity (MCAv) and prefrontal cerebral haemodynamics were measured with transcranial Doppler and near infrared spectroscopy, respectively. IH did not affect SRT and CRT performance from rest (566 ± 50 and 594 ± 70 ms), whereas PH (721 ± 51 and 765 ± 48 ms) and EH (718 ± 55 and 755 ± 34 ms) slowed response times (P < 0.001 vs. IH). Performance on the SWM task was not altered by condition. MCAv increased during IH compared to PH (P < 0.05), which was unchanged from rest. EH caused a significant fall in MCAv and prefrontal cerebral oxygenation (P < 0.05 vs. baseline). MCAv was moderately correlated to cognitive performance (R 2  = 0.266-0.289), whereas prefrontal cerebral tissue perfusion and saturation were not (P > 0.05). These findings reveal a role of hyperventilation-induced hypocapnia per se on the development of cognitive impairment during normoxic and hypoxic exposures., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

New Findings: What is the central question of this study? There is an interaction between the regulatory systems of respiration and cerebral blood flow, because the mediator (CO 2 ) is the same for both physiological systems. We examined whether the traditional method for determining cerebrovascular reactivity to CO 2 is modified by changes in respiration. What is the main finding and its importance? Cerebrovascular reactivity was modified by voluntary changes in respiration during hypercapnia. This finding suggests that an alteration in the respiratory system may result in under- or overestimation of cerebrovascular reactivity determined by traditional methods in healthy adults., Abstract: The cerebral vasculature is sensitive to changes in the arterial partial pressure of CO 2 . This physiological mechanism has been well established as a cerebrovascular reactivity to CO 2 (CVR). However, arterial CO 2 may not be an independent variable in the traditional method for assessment of CVR, because the cerebral blood flow response is also affected by the activation of respiratory drive or higher centres in the brain. We hypothesized that CVR is modified by changes in respiration. To test our hypothesis, in the present study, 10 young, healthy subjects performed hyper- or hypoventilation to change end-tidal CO 2 ( P ET , C O 2 ) with different concentrations of CO 2 in the inhaled gas (0, 2.0 and 3.5%). We measured middle cerebral artery mean blood flow velocity by transcranial Doppler ultrasonography to identify the cerebral blood flow response to change in P ET , C O 2 during each set of conditions. In each set of conditions, P ET , C O 2 was significantly altered by changes in ventilation, and middle cerebral artery mean blood flow velocity changed accordingly. However, the relationship between changes in middle cerebral artery mean blood flow velocity and P ET , C O 2 as a response curve of CVR was reset upwards and downwards by hypo- and hyperventilation, respectively, compared with CVR during normal ventilation. The findings of the present study suggest the possibility that an alteration in respiration might lead to under- or overestimation of CVR determined by the traditional methods., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Key Points: For small mammals living in a cold, hypoxic environment, supplying enough O 2 to sustain thermogenesis can be challenging. While heterothermic mammals are generally more tolerant of cold and hypoxia than homeothermic mammals, how they regulate O 2 supply and demand during progressive cooling in hypoxia is largely unknown. We show that as ambient temperature is reduced in hypoxia, body temperature falls in both homeotherms and heterotherms. In the homeothermic rat, a decrease in O 2 consumption rate and lung O 2 extraction accompany this fall in body temperature, despite a relative hyperventilation. Paradoxically, in heterothermic mice, hamsters and ground squirrels, body temperature decreases more than in the homeothermic rat, even though they maintain ventilation, increase lung O 2 extraction and maintain or elevate their O 2 consumption rates. Variation in cold and hypoxia tolerance among homeotherms and heterotherms reflects divergent strategies in how O 2 supply and demand are regulated under thermal and hypoxic challenges., Abstract: Compared to homeothermic mammals, heterothermic mammals are reported to be exceptionally tolerant of cold and hypoxia. We hypothesised that this variation in tolerance stems from divergent strategies in how homeotherms and heterotherms regulate O 2 supply versus O 2 demand when exposed to hypoxia during progressive cooling. To test this hypothesis, we exposed adult rodents ranging in their degree of heterothermic expression (homeotherm: rats, facultative heterotherms: mice and hamsters, and obligate heterotherm: ground squirrels) to either normoxia (21% O 2 ) or environmental hypoxia (7% O 2 ), while reducing ambient temperature from 38 to 5°C. We found that when ambient temperature was reduced in normoxia, all species increased their O 2 consumption rate and ventilation in parallel, maintaining a constant ventilatory equivalent and level of lung O 2 extraction. Surprisingly, body temperature fell in all species, significantly so in the heterotherms. When ambient temperature was reduced in hypoxia, however, the homeothermic rat decreased their O 2 consumption rate and lung O 2 extraction despite an increase in their ventilatory equivalent, indicative of a relative hyperventilation. Heterotherms (mice, hamsters and ground squirrels), on the other hand, decreased their ventilatory equivalent, but increased lung O 2 extraction and maintained or elevated their O 2 consumption rates, yet their body temperature fell even more than in the rat. These results are consistent with the idea that homeotherms and heterotherms diverge in the strategies they use to match O 2 supply and O 2 demand, and that enhanced cold and hypoxia tolerance in heterotherms may stem from an improved ability to extract O 2 from the inspired air., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

Objectives: The diagnosis of epilepsy can cause many problems, especially when the routine electrophysiological tests are inconclusive. The aim of the present study was to assess the visual evoked potential (VEP) in patients with epilepsy using various kinds of stimulation and activation tests. The VEP parameters were also presented with reference to the type of seizure and abnormalities in electroencephalogram (EEG), including the response to the activation tests., Materials and Methods: This study comprised 81 patients with newly diagnosed epilepsy of unknown etiology before initiation of the treatment. The VEP tests were performed at rest, after hyperventilation, and deprivation of sleep. Visual stimulation included an alternating checkerboard pattern and a uniform flash light (FL) with a frequency of 1.88 and 15 Hz., Results: The VEP parameters obtained with the stimulation of a checkerboard pattern did not differ significantly between the patients and controls. Neither the presence of seizure activity in EEG nor the type of seizure significantly affected the VEP parameters. Using the FL stimulation, a significantly prolonged VEP latency was found at the FL frequency of 1.88 Hz and shortened at the frequency of 15 Hz. These changes were augmented after activation tests. In case of the patients with positive intermittent photic stimulation response in EEG, a significant prolongation of P100 latency was shown at rest and after FL stimulation at the frequency of 1.88 Hz., Conclusion: Standard activation methods significantly affect the VEP parameters in patients with epilepsy. Changes in the VEP parameters depend on the frequency and the type of the stimulus, as well as the activation method used. These findings suggest a disturbed balance between the glutamatergic and GABAergic systems in the visual excitability of neuronal networks in case of patients with epilepsy., Competing Interests: None

Background: Dynamic lung hyperinflation (DLH) following metronome-paced incremental hyperventilation (MPIH) was reported to be useful for assessment of pathophysiological impairment in patients with chronic obstructive pulmonary disease (COPD), and the effects of tiotropium and olodaterol on DLH following MPIH have not been reported. Methods: Treatment consisted of administration of tiotropium/olodaterol 5/5 μg inhalation solution (2.5/2.5 μg per actuation) using a soft-mist inhaler once a day. We compared outcomes before and after 8 weeks of treatment. The primary outcome was defined as a decrease in inspiratory capacity (IC) from rest by MPIH, which is an index of DLH. The secondary outcomes were COPD assessment test (CAT), forced expiratory volume in 1 s (FEV 1 ), and 6-min walking distance (6MWD). In addition, we investigated whether there were correlations between changes with treatment in DLH and FEV 1 , 6MWD, and dyspnea. Results: Thirty-three of the 38 registered patients completed this study. Most of these 33 patients had mild to moderate COPD. Decreasing IC by MPIH was significantly reduced by treatment for 8 weeks, with a mean change of about -0.11 to -0.13 mL ( P  <0.05). In addition, CAT score, FEV 1 , and 6MWD improved with treatment ( P  <0.05). There were no significant correlations between changes in DLH, FEV 1 , 6MWD, or dyspnea with treatment. Conclusions: The results of this study showed that the combination of tiotropium and olodaterol is effective for improvement of DLH following hyperventilation., Competing Interests: The authors received financial support from Nihon rehabilitation Shinkokai Foundation, a general incorporated foundation (Koganei, Tokyo, Japan) for this study.  Keisaku Fujimoto reports grants from Murata Manufacturing Co., Ltd., Seiko Epson Corporation, Denso Corporation, Kanazawa Murata Manufacturing Co., and Koganei Corporation. He also received personal fees from Japan Association for the Advancement of Medical Equipment, Astellas Pharma Inc., AstraZeneca Co., Ltd., Fukuda Denshi Co., Ltd., Fukuda Lifetec Co., Ltd., GlaxoSmithKline Co., Ltd., Japan Respiratory Society, Kyorin Pharmaceutical Co., Ltd., MeijiSeika Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Teijin Home Healthcare Limited, and Teijin Pharma Limited. He further received grants and personal fees from MSD Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd. and Novartis Pharma Co., Ltd., outside the submitted work. The authors report no other conflicts of interest in this work.

Cough number and/or sound have been used to assess cough sensitivity/intensity and to discriminate cough patterns in clinical settings. However, to date, only manual counting of cough number in an offline manner is applied in animal cough studies, which diminishes the efficiency of cough identification and hinders the diagnostic discrimination of cough patterns, especially in animals with pulmonary diseases. This study aims to validate a novel recording/analysis system by which cough numbers are automatically counted and cough patterns are comprehensively differentiated in real time. The experiment was carried out in conscious guinea pigs exposed to aerosolized citric acid (CA, 150 mM) and prostaglandin E2 (PGE2, 0.43 mM). Animal body posture (video), respiratory flow, and cough acoustics (audio) were simultaneously monitored and recorded. Cough number was counted automatically, and cough sound parameters including waveform, duration, power spectral density, spectrogram, and intensity, were analyzed in real time. Our results showed that CA- and PGE2-evoked coughs had the same cough numbers but completely different patterns [individual coughs vs. bout(s) of coughs]. Compared to CA-evoked coughs, PGE2-evoked coughs possess a longer latency, higher cough rate (coughs/min), shorter cough sound duration, lower cough sound intensity, and distinct cough waveforms and spectrograms. A few mucus- and wheeze-like coughs were noted in response to CA but not to PGE2. In conclusion, our recording/analysis system is capable of automatically counting the cough number and successfully differentiating the cough pattern by using valuable cough sound indexes in real time. Our system enhances the objectivity, accuracy, and efficiency of cough identification and count, improves the intensity evaluation, and offers ability for pattern discrimination compared to traditional types of cough identification. Importantly, this approach is beneficial for assessing the efficacy of putative antitussive drugs in animals without or with pulmonary diseases, particularly in cases without significant change in cough number., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Measurement of ventilatory efficiency, defined as minute ventilation per unit carbon dioxide production (VE/VCO2), by cardiopulmonary exercise testing (CPET) has been proposed as a screen for hyperventilation syndrome (HVS). However, increased VE/VCO2 may be associated with other disorders which need to be distinguished from HVS. A more specific marker of HVS by CPET would be clinically useful. We hypothesized ventilatory control during exercise is abnormal in patients with HVS., Methods: Patients who underwent CPET from years 2015 through 2017 were retrospectively identified and formed the study group. HVS was defined as dyspnea with respiratory alkalosis (pH >7.45) at peak exercise with absence of acute or chronic respiratory, heart or psychiatric disease. Healthy patients were selected as controls. For comparison the Student t-test or Mann-Whitney U test were used. Data are summarized as mean ± SD or median (IQR); p<0.05 was considered significant., Results: Twenty-nine patients with HVS were identified and 29 control subjects were selected. At rest, end-tidal carbon dioxide (PETCO2) was 27 mmHg (25-30) for HVS patients vs. 30 mmHg (28-32); in controls (p = 0.05). At peak exercise PETCO2 was also significantly lower (27 ± 4 mmHg vs. 35 ± 4 mmHg; p<0.01) and VE/VCO2 higher ((38 (35-43) vs. 31 (27-34); p<0.01)) in patients with HVS. In contrast to controls, there were minimal changes of PETCO2 (0.50 ± 5.26 mmHg vs. 6.2 ± 4.6 mmHg; p<0.01) and VE/VCO2 ((0.17 (-4.24-6.02) vs. -6.6 (-11.4-(-2.8)); p<0.01)) during exercise in patients with HVS. The absence of VE/VCO2 and PETCO2 change during exercise was specific for HVS (83% and 93%, respectively)., Conclusion: Absence of VE/VCO2 and PETCO2 change during exercise may identify patients with HVS., Competing Interests: The authors have declared that no competing interests exist.

Background: Hyperventilation-induced hypocapnia (HV) reduces elevated intracranial pressure (ICP), a dangerous and potentially fatal complication of traumatic brain injury (TBI). HV decreases the arteriolar diameter of intracranial vessels, raising the risk of cerebral ischemia. The aim of this study was to characterize the effects of moderate short-term HV in patients with severe TBI by using concomitant monitoring of cerebral metabolism, brain tissue oxygen tension (PbrO 2 ), and cerebral hemodynamics with transcranial color-coded duplex sonography (TCCD)., Methods: This prospective trial was conducted between May 2014 and May 2017 in the surgical intensive care unit (ICU) at the University Hospital of Zurich. Patients with nonpenetrating TBI older than 18 years of age with a Glasgow Coma Scale (GCS) score < 9 at presentation and with ICP monitoring, PbrO 2 , and/or microdialysis (MD) probes during ICU admission within 36 h after injury were included in our study. Data collection and TCCD measurements were performed at baseline (A), at the beginning of moderate HV (C), after 50 min of moderate HV (D), and after return to baseline (E). Moderate HV was defined as arterial partial pressure of carbon dioxide 4-4.7 kPa. Repeated measures analysis of variance was used to compare variables at the different time points, followed by post hoc analysis with Bonferroni adjustment as appropriate., Results: Eleven patients (64% males, mean age 36 ± 14 years) with an initial median GCS score of 7 (IQR 3-8) were enrolled. During HV, ICP and mean flow velocity (CBFV) in the middle cerebral artery decreased significantly. Glucose, lactate, and pyruvate in the brain extracellular fluid did not change significantly, whereas PbrO 2 showed a statistically significant reduction but remained within the normal range., Conclusion: Moderate short-term hyperventilation has a potent effect on the cerebral blood flow, as shown by TCCD, with a concomitant ICP reduction. Under the specific conditions of this study, this degree of hyperventilation did not induce pathological alterations of brain metabolites and oxygenation., Trial Registration: NCT03822026 . Registered on 30 January 2019.

Dysfunctional breathing (DB) is a respiratory condition characterized by irregular breathing patterns that occur either in the absence of concurrent diseases or secondary to cardiopulmonary diseases. Although the primary symptom is often dyspnea or "air hunger", DB is also associated with nonrespiratory symptoms such as dizziness and palpitations. DB has been identified across all ages. Its prevalence among adults in primary care in the United Kingdom is approximately 9.5%. In addition, among individuals with asthma, a positive diagnosis of DB is found in a third of women and a fifth of men. Although DB has been investigated for decades, it remains poorly understood because of a paucity of high-quality clinical trials and validated outcome measures specific to this population. Accordingly, DB is often underdiagnosed or misdiagnosed, given the similarity of its associated symptoms (dyspnea, tachycardia, and dizziness) to those of other common cardiopulmonary diseases such as COPD and asthma. The high rates of misdiagnosis of DB suggest that health care professionals do not fully understand this condition and may therefore fail to provide patients with an appropriate treatment. Given the multifarious, psychophysiological nature of DB, a holistic, multidimensional assessment would seem the most appropriate way to enhance understanding and diagnostic accuracy. The present narrative review was developed as a means of summarizing the available evidence about DB, as well as improving understanding of the condition by researchers and practitioners.

Hyperthermia causes hyperventilation at rest and during exercise. We previously reported that carotid chemoreceptors partly contribute to the hyperthermia-induced hyperventilation at rest. However, given that a hyperthermia-induced hyperventilation markedly differs between rest and exercise, the results obtained at rest may not be representative of the response in exercise. Therefore, we evaluated whether carotid chemoreceptors contribute to hyperthermia-induced hyperventilation in exercising humans. Eleven healthy young men (23 ± 2 yr) cycled in the heat (37°C) at a fixed submaximal workload equal to ~55% of the individual's predetermined peak oxygen uptake (moderate intensity). To suppress carotid chemoreceptor activity, 30-s hyperoxia breathing (100% O 2 ) was performed at rest (before exercise) and during exercise at increasing levels of hyperthermia as defined by an increase in esophageal temperature of 0.5°C (low), 1.0°C (moderate), 1.5°C (high), and 2.0°C (severe) above resting levels. Ventilation during exercise gradually increased as esophageal temperature increased (all P ≤ 0.05), indicating that hyperthermia-induced hyperventilation occurred. Hyperoxia breathing suppressed ventilation in a greater manner during exercise (-9 to -13 l/min) than at rest (-2 ± 1 l/min); however, the magnitude of reduction during exercise did not differ at low (0.5°C) to severe (2.0°C) increases in esophageal temperature (all P > 0.05). Similarly, hyperoxia-induced changes in ventilation during exercise as assessed by percent change from prehyperoxic levels were not different at all levels of hyperthermia (~15-20%, all P > 0.05). We show that in young men carotid chemoreceptor contribution to hyperthermia-induced hyperventilation is relatively small at low-to-severe increases in body core temperature induced by moderate-intensity exercise in the heat. NEW & NOTEWORTHY Exercise-induced increases in hyperthermia cause a progressive increase in ventilation in humans. However, the mechanisms underpinning this response remain unresolved. We showed that in young men hyperventilation associated with exercise-induced hyperthermia is not predominantly mediated by carotid chemoreceptors. This study provides important new insights into the mechanism(s) underpinning the regulation of hyperthermia-induced hyperventilation in humans and suggests that factor(s) other than carotid chemoreceptors play a more important role in mediating this response.

Objective This study was performed to determine the usefulness of a newly developed spirometer for the quantitative assessment of dynamic lung hyperinflation (DLH) following incremental hyperventilation in chronic obstructive pulmonary disease (COPD). Methods The subjects were 54 patients with COPD and 25 healthy volunteers. Each subject was asked to hyperventilate for 30 seconds with stepwise increments starting at the resting respiration rate and increasing to respiratory rates of 20, 30, and finally 40 breaths/min while using a newly developed spirometer. The relationship between the observed inspiratory capacity (IC) reduction following incremental hyperventilation as an index of DLH and spirometry or the 6-minute walking distance was examined. Results The IC did not decrease significantly from the resting IC, even when the respiratory rate was increased, in the healthy volunteer group. However, in the COPD patient group, the IC decreased with increases in the respiratory rate. Significant correlations were found between all IC parameters and the severity of COPD. A significant negative correlation was also found between the decreased IC and the 6-minute walking distance. Conclusion These findings suggest that the quantitative assessment of DLH following incremental hyperventilation using the newly developed spirometer may be useful for the assessment of pathophysiological impairment in patients with COPD.

We investigated whether heat-induced hyperventilation can be voluntarily prevented, and, if so, how this modulates respiratory mechanics and cerebral blood flow in resting heated humans. In two separate trials, 10 healthy men were passively heated using lower body hot-water immersion and a water-perfused garment covering their upper body (both 41°C) until esophageal temperature (T es ) reached 39°C or volitional termination. In each trial, participants breathed normally (normal-breathing) or voluntarily controlled minute ventilation (V E ) at a level equivalent to that observed after 5 min of heating (controlled-breathing). Respiratory gases, middle cerebral artery blood velocity (MCAV), work of breathing, and end-expiratory and inspiratory lung volumes were measured. During normal-breathing, V E increased as T es rose above 38.0 ± 0.3°C, whereas controlled-breathing diminished the increase in V E (V E at T es  = 38.6°C: 25.6 ± 5.9 and 11.9 ± 1.3 L min -1 during normal- and controlled-breathing, respectively, P < 0.001). During normal-breathing, end-tidal CO 2 pressure and MCAV decreased with rising T es , but controlled-breathing diminished these reductions (at T es  = 38.6°C, 24.7 ± 5.0 vs. 39.5 ± 2.8 mmHg; 44.9 ± 5.9 vs. 60.2 ± 6.3 cm sec -1 , both P < 0.001). The work of breathing correlated positively with changes in V E (P < 0.001) and was lower during controlled- than normal-breathing (16.1 ± 12.6 and 59.4 ± 49.5 J min -1 , respectively, at heating termination, P = 0.013). End-expiratory and inspiratory lung volumes did not differ between trials (P = 0.25 and 0.71, respectively). These results suggest that during passive heating at rest, heat-induced hyperventilation increases the work of breathing without affecting end-expiratory lung volume, and that voluntary control of breathing can nearly abolish this hyperventilation, thereby diminishing hypocapnia, cerebral hypoperfusion, and increased work of breathing., (© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Loss of consciousness occurs in post-hyperventilation apnea, but its pathophysiology remains unclear. We herein report a patient with post-hyperventilation apnea showing spindle activity on electroencephalogram (EEG). The patient was alert and breathing spontaneously before the hyperventilation test, but loss of consciousness and apnea with spindle activity on EEG occurred when the end-tidal CO 2 decreased during the hyperventilation test. She recovered consciousness and spontaneous breathing with the disappearance of the spindle activity on EEG when the end-tidal CO 2 increased after the hyperventilation test. The loss of consciousness during post-hyperventilation apnea might be due to the focal involvement of the ascending-activating mesodiencephalic reticular formation.

Upright hyperventilation occurs in ~25% of our patients with postural tachycardia syndrome (POTS). Poikilocapnic hyperventilation alone causes tachycardia. Here, we examined changes in respiration and hemodynamics comprising cardiac output (CO), systemic vascular resistance (SVR), and blood pressure (BP) measured during head-up tilt (HUT) in three groups: patients with POTS and hyperventilation (POTS-HV), patients with panic disorder who hyperventilate (Panic), and healthy controls performing voluntary upright hyperpnea (Voluntary-HV). Though all were comparably tachycardic during hyperventilation, POTS-HV manifested hyperpnea, decreased CO, increased SVR, and increased BP during HUT; Panic patients showed both hyperpnea and tachypnea, increased CO, and increased SVR as BP increased during HUT; and Voluntary-HV were hyperpneic by design and had increased CO, decreased SVR, and decreased BP during upright hyperventilation. Mechanisms of hyperventilation and hemodynamic changes differed among POTS-HV, Panic, and Voluntary-HV subjects. We hypothesize that the hyperventilation in POTS is caused by a mechanism involving peripheral chemoreflex sensitization by intermittent ischemic hypoxia. NEW & NOTEWORTHY Hyperventilation is common in postural tachycardia syndrome (POTS) and has distinctive cardiovascular characteristics when compared with hyperventilation in panic disorder or with voluntary hyperventilation. Hyperventilation in POTS is hyperpnea only, distinct from panic in which tachypnea also occurs. Cardiac output is decreased in POTS, whereas peripheral resistance and blood pressure (BP) are increased. This is distinct from voluntary hyperventilation where cardiac output is increased and resistance and BP are decreased and from panic where they are all increased.

Vasomotor response is related to the capacity of the vessel to maintain vascular tone within a narrow range. Two main control mechanisms are involved: the autonomic control of the sympathetic neural drive (global control) and the endothelial smooth cells capacity to respond to mechanical stress by releasing vasoactive factors (peripheral control). The aim of this study was to evaluate the effects of respiratory muscle training (RMT) on vasomotor response, assessed by flow-mediated dilation (FMD) and heart rate variability, in young healthy females. The hypothesis was that RMT could enhance the balance between sympathetic and parasympathetic neural drive and reduce vessel shear stress. Thus, twenty-four women were randomly assigned to either RMT or SHAM group. Maximal inspiratory mouth pressure and maximum voluntary ventilation were utilized to assess the effectiveness of the RMT program, which consisted of three sessions of isocapnic hyperventilation/ week for eight weeks, (twenty-four training sessions). Heart rate variability assessed autonomic balance, a global factor regulating the vasomotor response. Endothelial function was determined by measuring brachial artery vasodilation normalized by shear rate (%FMD/SR). After RMT, but not SHAM, maximal inspiratory mouth pressure and maximum voluntary ventilation increased significantly (+31% and +16%, respectively). Changes in heart rate variability were negligible in both groups. Only RMT exhibited a significant increase in %FMD/SR (+45%; p<0.05). These data suggest a positive effect of RMT on vasomotor response that may be due to a reduction in arterial shear stress, and not through modulation of sympatho-vagal balance., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To study modulation of epileptiform EEG discharges in patients with JME., Method: 50 subjects with JME underwent a sleep deprived EEG recording along with conventional provocative methods and testing with cognitive tasks (CTs). Both categories of tests were evaluated for their effect on occurrence of IEDs. Number of IEDs per unit time was calculated at baseline as well as with each task. Statistical and arbitrary methods were used to assess modulation. By arbitrary method if frequency of IEDs was more than twice that of baseline, it was considered as provocation and if less than half, it was considered as inhibition. To account for spontaneous fluctuation of IEDs, 95% CI was calculated for baseline IEDs in each patient and provocation/inhibition was considered if frequency of IEDs exceeded/remained below limits of CI respectively., Results: There was no significant difference in rates of provocation of IEDs by conventional or CTs. However there was exclusive provocation of IEDs by CTs in 4 patients, 3 of whom were already on AEDs. There was a significant inhibitory effect of CTs as mean baseline discharge frequency was 0.4 ± 1.16 IEDS/min and during CTs was 0.1 ± 0.38 IEDs/min. However when spontaneous fluctuation was accounted for, inhibition was seen in only 22.23% patients by statistical method as compared to 90.91% by arbitrary method., Conclusions: Inclusion of CTs may assist in provocation of IEDs, thereby increasing yield of routine EEG. Spontaneous fluctuation of IEDs accounts for much observed inhibition by CTs in JME patients., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Postural tachycardia syndrome (POTS) is a heterogeneous condition. We stratified patients previously evaluated for POTS on the basis of supine resting cardiac output (CO) or with the complaint of platypnea or "shortness of breath" during orthostasis. We hypothesize that postural hyperventilation is one cause of POTS and that hyperventilation-associated POTS occurs when initial reduction in CO is sufficiently large. We also propose that circulatory abnormalities normalize with restoration of CO 2 ., Methods and Results: Fifty-eight enrollees with POTS were compared with 16 healthy volunteer controls. Low CO in POTS was defined by a resting supine CO <4 L/min. Patients with shortness of breath had hyperventilation with end tidal CO 2 <30 Torr during head-up tilt table testing. There were no differences in height or weight between control patients and patients with POTS or differences between the POTS groups. Beat-to-beat blood pressure was measured by photoplethysmography, and CO was measured by ModelFlow. Systemic vascular resistance was defined as mean arterial blood pressure/CO. End tidal CO 2 and cerebral blood flow velocity of the middle cerebral artery were only reduced during head-up tilt in the hyperventilation group, whereas blood pressure was increased compared with control. We corrected the reduced end tidal CO 2 in hyperventilation by addition of exogenous CO 2 into a rebreathing apparatus. With added CO 2 , heart rate, blood pressure, CO, and systemic vascular resistance in hyperventilation became similar to control., Conclusions: We conclude that all POTS is related to decreased CO, decreased central blood volume, and increased systemic vascular resistance and that a variant of POTS is consequent to postural hyperventilation., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Hyperventilation with a subsequent breath-hold has been successfully used as a non-pharmacological vasoactive stimulus to induce changes in myocardial oxygenation. The purpose of this pilot study was to assess if this maneuver is feasible in patients with multi-vessel coronary artery disease (CAD), and if it is effective at detecting coronary artery stenosis > 50% determined by quantitative coronary angiography (QCA)., Methods: Twenty-six patients with coronary artery stenosis (QCA > 50% diameter stenosis) underwent a contrast-free cardiovascular magnetic resonance (CMR) exam in the time interval between their primary coronary angiography and a subsequent percutaneous coronary intervention (PCI, n = 24) or coronary artery bypass (CABG, n = 2) revascularization procedure. The CMR exam involved standard function imaging, myocardial strain analysis, T2 mapping, native T1 mapping and oxygenation-sensitive CMR (OS-CMR) imaging. During OS-CMR, participants performed a paced hyperventilation for 60s followed by a breath-hold to induce a vasoactive stimulus. Ten healthy subjects underwent the CMR protocol as the control group., Results: All CAD patients completed the breathing maneuvers with an average breath-hold duration of 48 ± 23 s following hyperventilation and without any complications or adverse effects. In comparison to healthy subjects, CAD patients had a significantly attenuated global myocardial oxygenation response to both hyperventilation (- 9.6 ± 6.8% vs. -3.1 ± 6.5%, p = 0.012) and apnea (11.3 ± 6.1% vs. 2.1 ± 4.4%, p < 0.001). The breath-hold maneuver unmasked regional oxygenation differences in territories subtended by a stenotic coronary artery in comparison to remote territory within the same patient (0.5 ± 3.8 vs. 3.8 ± 5.3%, p = 0.011)., Conclusion: Breathing maneuvers in conjunction with OS-CMR are clinically feasible in CAD patients. Furthermore, OS-CMR demonstrates myocardial oxygenation abnormalities in regional myocardium related to CAD without the use of pharmacologic vasodilators or contrast agents. A larger trial appears warranted for a better understanding of its diagnostic utility., Trial Registration: Clinical Trials Identifier: NCT02233634 , registered 8 September 2014.

Background: Respiratory complaints after exercise are common in patients with rhinitis. Exercise-induced bronchospasm (EIB) may be one of the causes., Objectives: To evaluate EIB prevalence in a group of children and adolescents with allergic rhinitis, to compare the treadmill running (TR) and eucapnic voluntary hyperventilation (EVH) challenge methods as diagnostic tools and to assess the association between respiratory complaints on exercise and EIB., Methods: Patients aged between 10 and 20 years were studied at the Pulmonology Department of the Hospital das Clínicas -UFPE- Recife, Brazil. The severity of symptoms of rhinitis and exercise-related respiratory complaints in the past year were evaluated. Challenges were performed in random sequence, no more than 72 h apart and followed international guidelines. Forced expiratory volume in the first second (FEV1) was determined before and 3, 5, 7, 10, 15 and 30 min after each challenge. A >10% reduction in FEV1 from baseline at two points after the challenge was considered sufficient to diagnose EIB., Results: Of the thirty-five subjects evaluated, thirteen (37%) showed EIB, six by both methods, three only after TR and four only after EVH (Coens' Kappa = 0.489). There was no association between respiratory complaints after exercise and EIB (p = 0.74)., Conclusion: A high prevalence of EIB was found in this population but only moderate agreement between the challenges used to diagnose EIB. Caution should be adopted when comparing these methods or interpreting their results interchangeably. There was no association between reported respiratory symptoms after exercise and EIB., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

New Findings: What is the central question of this study? The lack of useful small-animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states. What is the main finding and its importance? We developed an anaesthetized-rat model for studying exercise hyperpnoea, using a respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models., Abstract: Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiological basis of various disease models, the lack of an integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anaesthetized-rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anaesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO 2 pressure (P ETC O2) and minute ventilation (V̇E), and the plant by the hyperbolic relationship between V̇E and P ETC O2. During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen uptake. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points (V̇E and P ETC O2) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anaesthetized-rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models., (© 2018 Morinomiya University of Medical Sciences. Experimental Physiology © 2018 The Physiological Society.)

Mutations or deletions of the transcription factor TCF4 are linked to Pitt-Hopkins syndrome (PTHS) and schizophrenia, suggesting that the precise pathogenic mutations dictate cellular, synaptic, and behavioral consequences. Here, we generated two novel mouse models of PTHS, one that mimics the most common pathogenic TCF4 point mutation (human R580W, mouse R579W) and one that deletes three pathogenic arginines, and explored phenotypes of these lines alongside models of pan-cellular or CNS-specific heterozygous Tcf4 disruption. We used mice of both sexes to show that impaired Tcf4 function results in consistent microcephaly, hyperactivity, reduced anxiety, and deficient spatial learning. All four PTHS mouse models demonstrated exaggerated hippocampal long-term potentiation (LTP), consistent with deficits in hippocampus-mediated behaviors. We further examined R579W mutant mice and mice with pan-cellular Tcf4 heterozygosity and found that they exhibited hippocampal NMDA receptor hyperfunction, which likely drives the enhanced LTP. Together, our data pinpoint convergent neurobiological features in PTHS mouse models and provide a foundation for preclinical studies and a rationale for testing whether NMDAR antagonists might be used to treat PTHS. SIGNIFICANCE STATEMENT Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder associated with TCF4 mutations/deletions. Despite this genetic insight, there is a need to identify the function of TCF4 in the brain. Toward this goal, we developed two mouse lines, including one harboring the most prevalent pathogenic point mutation, and compared them with two existing models that conditionally delete Tcf4 Our data identify a set of overlapping phenotypes that may serve as outcome measures for preclinical studies of PTHS treatments. We also discovered penetrant enhanced synaptic plasticity across mouse models that may be linked to increased NMDA receptor function. These data reveal convergent neurobiological characteristics of PTHS mouse models and support the further investigation of NMDA receptor antagonists as a possible PTHS treatment., (Copyright © 2018 the authors 0270-6474/18/380918-19$15.00/0.)

Elevating core temperature at rest causes increases in minute ventilation (V̇e), which lead to reductions in both arterial CO 2 partial pressure (hypocapnia) and cerebral blood flow. We tested the hypothesis that in resting heated humans this hypocapnia diminishes the ventilatory sensitivity to rising core temperature but does not explain a large portion of the decrease in cerebral blood flow. Fourteen healthy men were passively heated using hot-water immersion (41°C) combined with a water-perfused suit, which caused esophageal temperature (T es ) to reach 39°C. During heating in two separate trials, end-tidal CO 2 partial pressure decreased from the level before heating (39.4 ± 2.0 mmHg) to the end of heating (30.5 ± 6.3 mmHg) ( P = 0.005) in the Control trial. This decrease was prevented by breathing CO 2 -enriched air throughout the heating such that end-tidal CO 2 partial pressure did not differ between the beginning (39.8 ± 1.5 mmHg) and end (40.9 ± 2.7 mmHg) of heating ( P = 1.00). The sensitivity to rising T es (i.e., slope of the T es  - V̇ E relation) did not differ between the Control and CO 2 -breathing trials (37.1 ± 43.1 vs. 16.5 ± 11.1 l·min -1 ·°C -1 , P = 0.31). In both trials, middle cerebral artery blood velocity (MCAV) decreased early during heating (all P < 0.01), despite the absence of hyperventilation-induced hypocapnia. CO 2 breathing increased MCAV relative to Control at the end of heating ( P = 0.005) and explained 36.6% of the heat-induced reduction in MCAV. These results indicate that during passive heating at rest ventilatory sensitivity to rising core temperature is not suppressed by hypocapnia and that most of the decrease in cerebral blood flow occurs independently of hypocapnia. NEW & NOTEWORTHY Hyperthermia causes hyperventilation and concomitant hypocapnia and cerebral hypoperfusion. The last may underlie central fatigue. We are the first to demonstrate that hyperthermia-induced hyperventilation is not suppressed by the resultant hypocapnia and that hypocapnia explains only 36% of cerebral hypoperfusion elicited by hyperthermia. These new findings advance our understanding of the mechanisms controlling ventilation and cerebral blood flow during heat stress, which may be useful for developing interventions aimed at preventing central fatigue during hyperthermia.

Cerebrovascular CO 2 reactivity is affected by nitric oxide (NO). We tested the hypothesis that sildenafil selectively potentiates NO-cGMP signaling, which affects CO 2 reactivity. Fourteen healthy males (34 ± 2 yr) were enrolled in the study. Blood pressure (BP), ECG, velocity of cerebral blood flow (CBF; measured by transcranial Doppler), and end-tidal CO 2 (EtCO 2 ) were assessed at baseline (CO 2 ~39 mmHg), during hyperventilation (CO 2 ~24 mmHg), during hypercapnia (CO 2 ~46 mmHg), during boluses of phenylephrine (25-200 µg), and during graded head-up tilting (HUT). Measurements were repeated 1 h after 100 mg sildenafil were taken. Results showed that sildenafil did not affect resting BP, heart rate, CBF peak and mean velocities, estimated regional cerebrovascular resistance (eCVR; mean BP/mean CBF), breath/min, and EtCO 2 : 117 ± 2/67 ± 3 mmHg, 69 ± 3 beats/min, 84 ± 5 and 57 ± 4 cm/s, 1.56 ± 0.1 mmHg·cm -1 ·s -1 , 14 ± 0.5 breaths/min, and 39 ± 0.9 mmHg, respectively. Sildenafil increased and decreased the hypercapnia induced in CBF and eCVR, respectively. Sildenafil also attenuated the decrease in peak velocity of CBF, 25 ± 2 vs. 20 ± 2% ( P < 0.05) and increased the eCVR, 2.5 ± 0.2 vs. 2 ± 0.2% ( P < 0.03) during hyperventilation. Sildenafil did not affect CBF despite significant increases in the eCVRs that were elicited by phenylephrine and HUT. This investigation suggests that sildenafil, which potentiates the NO-cGMP signaling, seems to affect the cerebrovascular CO 2 reactivity without affecting the static and dynamic pressure-dependent mechanisms of cerebrovascular autoregulation., (Copyright © 2017 the American Physiological Society.)

Little is known about the response of the cerebrovasculature to acute exercise in children and how these responses might differ with adults. Therefore, we compared changes in middle cerebral artery blood velocity (MCAV mean ), end-tidal Pco 2 ([Formula: see text]), blood pressure, and minute ventilation (V̇e) in response to incremental exercise between children and adults. Thirteen children [age: 9 ± 1 (SD) yr] and thirteen sex-matched adults (age: 25 ± 4 yr) completed a maximal exercise test, during which MCAV mean , [Formula: see text], and V̇e were measured continuously. These variables were measured at rest, at exercise intensities specific to individual ventilatory thresholds, and at maximum. Although MCAV mean was higher at rest in children compared with adults, there were smaller increases in children (1-12%) compared with adults (12-25%) at all exercise intensities. There were alterations in [Formula: see text] with exercise intensity in an age-dependent manner [ F (2.5,54.5) = 7.983, P < 0.001; η 2 = 0.266], remaining stable in children with increasing exercise intensity (37-39 mmHg; P > 0.05) until hyperventilation-induced reductions following the respiratory compensation point. In adults, [Formula: see text] increased with exercise intensity (36-45 mmHg, P < 0.05) until the ventilatory threshold. From the ventilatory threshold to maximum, adults showed a greater hyperventilation-induced hypocapnia than children. These findings show that the relative increase in MCAV mean during exercise was attenuated in children compared with adults. There was also a weaker relationship between MCAV mean and [Formula: see text] during exercise in children, suggesting that cerebral perfusion may be regulated by different mechanisms during exercise in the child. NEW & NOTEWORTHY These findings provide the first direct evidence that exercise increases cerebral blood flow in children to a lesser extent than in adults. Changes in end-tidal CO 2 parallel changes in cerebral perfusion in adults but not in children, suggesting age-dependent regulatory mechanisms of cerebral blood flow during exercise., (Copyright © 2017 the American Physiological Society.)

Background: Oxygenation-sensitive cardiovascular magnetic resonance imaging (OS-CMR) is an emerging technique that can monitor changes in myocardial oxygenation in vivo. Obstructive sleep apnea syndrome (OSAS) is associated with endothelial and microcirculatory dysfunction and increased cardiovascular morbidity and mortality. Little is known about myocardial responses to apnea in patients with OSAS. We hypothesized that the coronary vascular response to hyperventilation and long breath-hold is diminished in patients with OSAS when compared to healthy volunteers., Methods: Twenty-nine OSAS patients and 36 healthy volunteers were prospectively enrolled. All CMR scans were performed on a clinical 3T system. Participants performed a breathing maneuver with 60s of hyperventilation followed by a maximal breath-hold. During the breath-hold, OS-CMR images were continuously acquired and signal intensity changes were measured by a blinded reader., Results: Patients with OSAS were older than healthy volunteers (p<0.01) and presented more co-morbidities; 66% were currently treated with nocturnal positive airway pressure. Compared to healthy participants, the expected increase of myocardial oxygenation during the first 15s of the breath-hold was significantly lower in patients with OSAS (2.6±8.3% vs. 6.7±5.6%; p<0.05), and remained reduced at all time points during the breath-hold. Importantly this result was mainly driven by patients under continuous positive airway pressure (CPAP), suggesting that CPAP might have a greater impact on increase of myocardial oxygenation rather than OSAS itself., Conclusions: The myocardial vascular response to combined breathing maneuvers of hyperventilation followed by voluntary apnea is blunted in patients with obstructive sleep apnea. Clinical studies should now further define the clinical role of oxygenation-sensitive CMR in patients with respiratory disorders., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: Dysfunctional breathing (DB) is a respiratory disorder, which involves a pattern of breathing too deeply, too superficially and/or too rapidly. In asthma patients, DB may lead to an overestimation of the severity of asthma symptoms, and hence potentially to overtreatment. However, it is not known to which degree DB may affect estimates of asthma control, in a specialist clinical setting., Methods: The MAPOut-study examined all patients referred consecutively over a 12-months period for specialist assessment of asthma at the Respiratory Outpatient Clinic at Bispebjerg Hospital in Copenhagen. All patients were examined with the Nijmegen questionnaire with a DB defined as a score ≥23 and the ACQ questionnaire. Linear regression analysis of predictors of ACQ score was performed. Asthma was defined as asthma symptoms and a positive asthma test., Results: Of the 256 patients referred to the lung clinic, data on both the Nijmegen questionnaire and ACQ score was obtained in 127 patients, who were included in the present analysis. Median (range) age: 30 (15-63) years, and 76 (59.8%) were females. DB was found in 31 (24.4%). Asthmatic patients with co-existing DB had a poorer asthma control compared to asthmatics without DB (Median (range) ACQ score: 2.40 (0.20-4.60) vs 1.20 (0.00-4.40); p < 0.001.). A regression analysis showed that the effect of DB on asthma control was independent of airway hyperresponsiveness or airway inflammation in patients with DB., Conclusion: Dysfunctional breathing is common among asthma patients in a specialist setting, and results in a clinically significant underestimation of asthma control, which may potentially lead to overtreatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Endurance athletes have a high prevalence of airway diseases, some possibly representing adaptive mechanisms to the need of conditioning large volumes of inspired air during high ventilation in specific environments. The aim of this study is to assess the ability to condition (warm and humidify) inspired air in athletes by measuring the difference between inhaled and exhaled air temperature (ΔT) during and after eucapnic voluntary hyperpnea (EVH) test., Methods: Twenty-three endurance athletes from various sports, 12 with airway hyperresponsiveness (AHR) and/or exercise-induced bronchoconstriction (EIB) (A+), 11 without AHR and/or EIB (A-), 12 nonathletes with AHR and/or EIB (C+), and 11 nonathletes without AHR and/or EIB (C-) were recruited. All subjects attended the laboratory on three occasions, twice for baseline characterization, including questionnaires, pulmonary function, methacholine bronchoprovocation, allergy skin prick tests, exhaled nitric oxide measurement, and a standard EVH, and once to perform a modified EVH to assess ΔT. Inspired and expired air temperatures were measured with a high-precision probe during EVH and at regular intervals until 30 min after the end of the test., Results: The global ΔT during the EVH was +5.8°C ± 1.5°C and +4.7°C ± 1.5°C during the 30 min after the EVH. No difference was found between groups for either the ΔT or the slope of ΔT, during and after the EVH., Conclusion: This study shows no evidence of improved capacity to condition inspired air in endurance athletes, which could have suggested an increased bronchial blood flow or another adaptive mechanism. The absence of an adaptive mechanism could therefore contribute to airway damage observed in athletes in allowing colder but mainly dryer air to penetrate deeper in the lung.

Background: Breathing maneuvers can elicit a similar vascular response as vasodilatory agents like adenosine; yet, their potential diagnostic utility in the presence of coronary artery stenosis is unknown. The objective of the study is to investigate if breathing maneuvers can non-invasively detect inducible ischemia in an experimental animal model when the myocardium is imaged with oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR)., Methods and Findings: In 11 anesthetised swine with experimentally induced significant stenosis (fractional flow reserve <0.75) of the left anterior descending coronary artery (LAD) and 9 control animals, OS-CMR at 3T was performed during two different breathing maneuvers, a long breath-hold; and a combined maneuver of 60s of hyperventilation followed by a long breath-hold. The resulting change of myocardial oxygenation was compared to the invasive measurements of coronary blood flow, blood gases, and oxygen extraction. In control animals, all breathing maneuvers could significantly alter coronary blood flow as hyperventilation decreased coronary blood flow by 34±23%. A long breath-hold alone led to an increase of 97±88%, while the increase was 346±327% (p<0.001), when the long breath-hold was performed after hyperventilation. In stenosis animals, the coronary blood flow response was attenuated after both hyperventilation and the following breath-hold. This was matched by the observed oxygenation response as breath-holds following hyperventilation consistently yielded a significant difference in the signal of the MRI images between the perfusion territory of the stenosis LAD and remote myocardium. There was no difference between the coronary territories during the other breathing maneuvers or in the control group at any point., Conclusion: In an experimental animal model, the response to a combined breathing maneuver of hyperventilation with subsequent breath-holding is blunted in myocardium subject to significant coronary artery stenosis. This maneuver may allow for detecting severe coronary artery stenosis and have a significant clinical potential as a non-pharmacological method for diagnostic testing in patients with suspected coronary artery disease., Competing Interests: Matthias G. Friedrich, Dominik Guensch and Kady Fischer hold a pending U.S. patent regarding the use of breathing maneuvers for diagnostics purpose (“Inducing and measuring myocardial oxygenation changes as a marker for heart disease”, Serial No. PCT/CA2013/050608). Matthias G. Friedrich is also a board member, advisor and shareholder of Circle Cardiovascular Imaging Inc., the manufacturer of the software used for CMR image evaluation. There are no other conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Key Points: We studied healthy astronauts before, during and after the Neurolab Space Shuttle mission with controlled breathing and apnoea, to identify autonomic changes that might contribute to postflight orthostatic intolerance. Measurements included the electrocardiogram, finger photoplethysmographic arterial pressure, respiratory carbon dioxide levels, tidal volume and peroneal nerve muscle sympathetic activity. Arterial pressure fell and then rose in space, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations rose and then fell in space, and descended to preflight levels upon return to Earth. Sympathetic burst frequencies (but not areas) were greater than preflight in space and on landing day, and astronauts' abilities to modulate both burst areas and frequencies during apnoea were sharply diminished. Spaceflight triggers long-term neuroplastic changes reflected by reciptocal sympathetic and vagal motoneurone responsiveness to breathing changes., Abstract: We studied six healthy astronauts five times, on Earth, in space on the first and 12th or 13th day of the 16 day Neurolab Space Shuttle mission, on landing day, and 5-6 days later. Astronauts followed a fixed protocol comprising controlled and random frequency breathing and apnoea, conceived to perturb their autonomic function and identify changes, if any, provoked by microgravity exposure. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, tidal carbon dioxide concentrations and volumes, and peroneal nerve muscle sympathetic activity on Earth (in the supine position) and in space. (Sympathetic nerve recordings were made during three sessions: preflight, late mission and landing day.) Arterial pressure changed systematically from preflight levels: pressure fell during early microgravity exposure, rose as microgravity exposure continued, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations (root mean square of successive normal R-R intervals; and proportion of successive normal R-R intervals greater than 50 ms, divided by the total number of normal R-R intervals) rose significantly during early microgravity exposure, fell as microgravity exposure continued, and descended to preflight levels upon return to Earth. Sympathetic mechanisms also changed. Burst frequencies (but not areas) during fixed frequency breathing were greater than preflight in space and on landing day, but their control during apnoea was sharply altered: astronauts increased their burst frequencies from already high levels, but they could not modulate either burst areas or frequencies appropriately. Space travel provokes long-lasting sympathetic and vagal neuroplastic changes in healthy humans., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Key Points: We studied healthy supine astronauts on Earth with electrocardiogram, non-invasive arterial pressure, respiratory carbon dioxide concentrations, breathing depth and sympathetic nerve recordings. The null hypotheses were that heart beat interval fluctuations at usual breathing frequencies are baroreflex mediated, that they persist during apnoea, and that autonomic responses to apnoea result from changes of chemoreceptor, baroreceptor or lung stretch receptor inputs. R-R interval fluctuations at usual breathing frequencies are unlikely to be baroreflex mediated, and disappear during apnoea. The subjects' responses to apnoea could not be attributed to changes of central chemoreceptor activity (hypocapnia prevailed); altered arterial baroreceptor input (vagal baroreflex gain declined and muscle sympathetic nerve burst areas, frequencies and probabilities increased, even as arterial pressure climbed to new levels); or altered pulmonary stretch receptor activity (major breathing frequency and tidal volume changes did not alter vagal tone or sympathetic activity). Apnoea responses of healthy subjects may result from changes of central respiratory motoneurone activity., Abstract: We studied eight healthy, supine astronauts on Earth, who followed a simple protocol: they breathed at fixed or random frequencies, hyperventilated and then stopped breathing, as a means to modulate and expose to view important, but obscure central neurophysiological mechanisms. Our recordings included the electrocardiogram, finger photoplethysmographic arterial pressure, tidal volume, respiratory carbon dioxide concentrations and peroneal nerve muscle sympathetic activity. Arterial pressure, vagal tone and muscle sympathetic outflow were comparable during spontaneous and controlled-frequency breathing. Compared with spontaneous, 0.1 and 0.05 Hz breathing, however, breathing at usual frequencies (∼0.25 Hz) lowered arterial baroreflex gain, and provoked smaller arterial pressure and R-R interval fluctuations, which were separated by intervals that were likely to be too short and variable to be attributed to baroreflex physiology. R-R interval fluctuations at usual breathing frequencies disappear during apnoea, and thus cannot provide evidence for the existence of a central respiratory oscillation. Apnoea sets in motion a continuous and ever changing reorganization of the relations among stimulatory and inhibitory inputs and autonomic outputs, which, in our study, could not be attributed to altered chemoreceptor, baroreceptor, or pulmonary stretch receptor activity. We suggest that responses of healthy subjects to apnoea are driven importantly, and possibly prepotently, by changes of central respiratory motoneurone activity. The companion article extends these observations and asks the question, Might terrestrial responses to our 20 min breathing protocol find expression as long-term neuroplasticity in serial measurements made over 20 days during and following space travel?, (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)